title: Smad2-dependent protease nexin-1 overexpression differentiates chronic aneurysms from acute dissections of human ascending aorta.
abstract: OBJECTIVE
  Tissue activation of proteolysis is involved in acute intramural rupture (dissections, acute ascending aortic dissection) and in progressive dilation (aneurysms, thoracic aneurysm of the ascending aorta) of human ascending aorta. The translational aim of this study was to characterize the regulation of antiproteolytic serpin expression in normal, aneurysmal, and dissecting aorta.
  
  
  RESULTS
  We explored expression of protease nexin-1 (PN-1) and plasminogen activator inhibitor-1 and their regulation by the Smad2 signaling pathway in human tissue and cultured vascular smooth muscle cells (VSMCs) of aneurysms (thoracic aneurysm of the ascending aorta; n=46) and acute dissections (acute ascending aortic dissection; n=10) of the ascending aorta compared with healthy aortas (n=10). Both PN-1 and plasminogen activator inhibitor-1 mRNA and proteins were overexpressed in medial tissue extracts and primary VSMC cultures from thoracic aneurysm of the ascending aorta compared with acute ascending aortic dissection and controls. Transforming growth factor-β induced increased PN-1 expression in control but not in aneurysmal VSMCs. PN-1 and plasminogen activator inhibitor-1 overexpression by aneurysmal VSMCs was associated with increased Smad2 binding on their promoters and, functionally, resulted in VSMC self-protection from plasmin-induced detachment and death. This phenomenon was restricted to aneurysms and not observed in acute dissections.
  
  
  CONCLUSIONS
  These results demonstrate that epigenetically regulated PN-1 overexpression promotes development of an antiproteolytic VSMC phenotype and might favor progressive aneurysmal dilation, whereas absence of this counter-regulation in dissections would lead to acute wall rupture.
authors.affiliation: Inserm, UMR 698, Paris 7-Denis Diderot University, CHU X. Bichat, Paris, France
authors.forename: Delphine
authors.initials: D
authors.lastname: Gomez
authors.forename: Ketty
authors.initials: K
authors.lastname: Kessler
authors.forename: Luciano F
authors.initials: LF
authors.lastname: Borges
authors.forename: Benjamin
authors.initials: B
authors.lastname: Richard
authors.forename: Ziad
authors.initials: Z
authors.lastname: Touat
authors.forename: Véronique
authors.initials: V
authors.lastname: Ollivier
authors.forename: Silvana
authors.initials: S
authors.lastname: Mansilla
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Bouton
authors.forename: Soleyman
authors.initials: S
authors.lastname: Alkoder
authors.forename: Patrick
authors.initials: P
authors.lastname: Nataf
authors.forename: Martine
authors.initials: M
authors.lastname: Jandrot-Perrus
authors.forename: Guillaume
authors.initials: G
authors.lastname: Jondeau
authors.forename: Roger
authors.initials: R
authors.lastname: Vranckx
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Michel
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000784:Aortic Dissection / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017545:Aortic Aneurysm, Thoracic / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001021:Aortic Valve / Q000002:abnormalities; D000082882:Bicuspid Aortic Valve Disease; D001665:Binding Sites; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D002908:Chronic Disease; D005260:Female; D000071837:Fibrillins; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006349:Heart Valve Diseases / Q000150:complications; D006801:Humans; D008297:Male; D008382:Marfan Syndrome / Q000150:complications / Q000235:genetics; D008840:Microfilament Proteins / Q000235:genetics; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D012307:Risk Factors; D058258:Serpin E2 / Q000235:genetics / Q000378:metabolism*; D051899:Smad2 Protein / Q000378:metabolism*; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D000071837:Fibrillins; D008840:Microfilament Proteins; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; C051321:SERPINE1 protein, human; C545486:SERPINE2 protein, human; C497782:SMAD2 protein, human; D058258:Serpin E2; D051899:Smad2 Protein; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1
keywords: Marfan syndrome; epigenomics; fibrinolysin; plasminogen activator inhibitor-1; serpins; smooth muscle cell